Synthesis and crystal structure studies of 5-(trifluoromethyl)-1,3,4-thiadiazol-2(3H)-one at 180 K

The synthesis and crystal structure of 5-(trifluoromethyl)-1,3,4-thiadiazol-2(3H)-one, a heterocycle of importance as a pharmaceutical building block, are presented.

The synthesis and crystal structure of C 3 HF 3 N 2 OS, systematic name 5-(trifluoromethyl)-1,3,4-thiadiazol-2(3H)-one (5-TMD-2-one), a compound containing the pharmacologically important heterocycle 1,3,4-thiadiazole, is presented. The asymmetric unit comprises six independent molecules (Z 0 = 6), all of which are planar. The r.m.s. deviations from each mean plane range from 0.0063 to 0.0381 Å , not including the CF 3 fluorine atoms. Within the crystal, two of the molecules form hydrogen-bonded dimers that in turn combine with inversion-related copies to form tetrameric constructs. Similar tetramers, but lacking inversion symmetry, are formed by the remaining four molecules. The tetramers are linked into tape-like motifs by SÁ Á ÁO and OÁ Á ÁO close contacts. The environments of each symmetry-independent molecule were compared via a Hirshfeld surface analysis. The most abundant atom-atom contacts are between fluorine atoms, while the strongest result from N-HÁ Á ÁO hydrogen bonds.
Overall, the 1,3,4-thiadiazole heterocycle provides the basis of a promising area of research in medicinal chemistry and drug discovery, with a wide range of potential applications. The reported findings provide insights into the molecular properties and biological activities of 1,3,4-thiadiazole derivatives, contributing to the development of novel therapeutic agents. With the importance of 1,3,4-thiadiazoles in drug discovery research in mind, this paper reports the synthesis and crystal structure of 5-(trifluoromethyl)-1,3,4-thiadiazol-2(3H)-one, C 3 HF 3 N 2 OS (5-TMD-2-one).

Structural commentary
The molecular structure of 5-TMD-2-one consists of a 1,3,4thiadiazone ring, essentially a flat pentagonal heterocycle with two adjacent nitrogen atoms, each flanked by carbon atoms, with a sulfur atom completing the ring. The simplicity of the molecular structure notwithstanding, the crystal structure of 5-TMD-2-one is far more complex, as the asymmetric unit contains six molecules (Z 0 = 6; designated A-F in Fig. 1). In each molecule, one of the nitrogen atoms (N1) carries a hydrogen atom and is single bonded to C1, while N2 is double bonded to C2. Atom C1 forms a carbonyl group with O1, and C2 carries a trifluoromethyl substituent. Deviations (r.m.s.) from planarity range from 0.0063 Å in molecule B to 0.0381 Å in molecule D, with the largest deviation for any atom (aside from fluorine), being 0.065 (8) Å for C3D, the trifluoromethyl carbon of molecule D. The only internal degree of freedom is the torsion of the trifluoromethyl group, which is disordered in all six symmetry-independent molecules in the structure. Indeed, the CF 3 orientations and the refined occupancies of the disorder components, which range from 0.500 (5):0.500 (5) for molecule D to 0.908 (2):0.092 (2) for molecule F, are the only significant differences between the six molecules.
The crystals were observed to shatter when cooled to 90 K, but remained intact and gave sharp diffraction at 180 K. This observation prompted us to investigate whether warming the crystals might lead to a simpler crystal structure, i.e., with fewer molecules in the asymmetric unit. A crystal mounted at room temperature, however, indexed to give essentially the same unit cell and structure (again with Z 0 = 6) as at 180 K.

Supramolecular features
The main supramolecular constructs in crystals of 5-TMD-2one are hydrogen-bonded tetramers. There are, however, slight differences for tetramers formed by molecules A and B (with inversion-related copies) and by molecules C, D, E and F. Within the chosen asymmetric unit, molecules A and B are joined by one short N1A-H1AÁ Á ÁO1B [d D-A = 2.726 (2) Å ] and one longer N1B-H1BÁ Á ÁO1A [d D-A = 3.328 (2) Å ] hydrogen bond, leading to R 2 2 (8) dimer motifs. Pairs of these dimers are connected to inversion-related copies by N1B-H1BÁ Á ÁO1A i [d D-A = 2.955 (2) Å ; symmetry code: (i) 2 À x, 1 À y, 1 À z] hydrogen bonds, producing R 2 2 (4) motifs in which the hydrogen atoms act as bifurcated donors (Fig. 2) A partial packing plot of 5-TMD-2-one viewed down the c-axis for the A and B molecules, showing N-HÁ Á ÁO hydrogen bonds (dashed lines) and intermolecular contacts (SÁ Á ÁO and OÁ Á ÁO, dotted lines), forming a tapelike motif parallel to (011) that extends along the a-axis direction. The hydrogen bonding and intermolecular contacts for molecules C, D, E and F are similar, but lack crystallographically imposed inversion symmetry.

Figure 1
An ellipsoid plot (30% probability) of the asymmetric unit of 5-TMD-2one. The CF 3 groups on all six independent molecules are disordered over two orientations, but only the major components are shown. and O1BÁ Á ÁO1B ii = 2.996 (3) Å ; symmetry code: (ii) 1 À x, 1 À y, 1 À z] contacts, forming tape-like structures parallel to (011) that extend along the [100] direction. For molecules C, D, E and F, the individual motifs are similar (see Table 1), but lack the constraints of inversion symmetry, leading to tapes with a slightly V-shaped cross section, as shown in Fig. 3. Owing to the complexity, however, the overall packing is best viewed using a molecular graphics program such as Mercury (Macrae et al., 2020). Hydrogen bonding and close-contact distances are given in Table 1.
Atom-atom contact two-dimensional fingerprint plots calculated using CrystalExplorer (Spackman et al., 2021) for each of the six independent molecules show that their environments are similar ( Fig. 4a-f). The most abundant contacts in each case are FÁ Á ÁF (shown in blue and green), ranging from 39.8% in molecule A (Fig. 4a) to 25.6% in molecule E (Fig. 4e).
Although crystal structures with Z 0 > 1 are not uncommon, their scarcity increases with Z 0 . In a detailed survey of structures with high Z 0 , Brock (2016) estimated that only about 12% of structures in the Cambridge Structural Database at the time (CSD; Groom et al., 2016) had Z 0 > 1, and < 0.1% had Z 0 > 4. Without any attempt to filter duplicates or pathological cases, in the current version of the CSD (v5.43, vide supra) there are 655 entries with Z 0 = 6 out of over 1.2 million ($0.05%), so by this criterion alone, the structure of 5-TMD-2-one is unusual, though not unprecedented.

Synthesis, crystallization and spectroscopic details
Synthesis of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole To a clean and dry 1 L round-bottom flask, 14.5 g of thiosemicarbazide suspended in 500 ml of 1,4 dioxane was added, A partial packing plot of 5-TMD-2-one viewed down the a-axis, showing the main difference between the A/B tape motif and those formed by molecules C, D, E and F, which have a shallow V-shaped cross section.
with stirring. 12.0 ml of CF 3 COOH and 15.0 mL of POCl 3 were slowly added over about 30 min. The reaction was maintained for 3 h, during which time, a large amount of HCl gas was produced. After completion of HCl gas liberation, the reaction mixture was poured into 100 mL of cold water with stirring and the pH adjusted to 9 with 50% NaOH solution, to give a solid precipitate. The product, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole, was filtered, washed with cold water and dried at 363 K (20.6 g).

Synthesis of 5-TMD-2-one
In a 250 ml round-bottomed flask, 20.6 g of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole was suspended with 150 ml conc. hydrochloric acid, with stirring. The reaction mixture was cooled to between 263 and 268 K. Then, 350 mL of aqueous NaNO 2 were added slowly (21.2 g, 0.307 mol, 4 eq.) while maintaining the temperature at 263-268 K with continued stirring. After 2 h, 100 ml of H 2 O were added with warming up to 333-353 K and stirred for a further 3 h. The reaction mixture was then cooled to room temperature, 150 mL of CH 2 Cl 2 were added, the organic layer separated and a further 150 ml CH 2 Cl 2 were added. The combined organic layers were washed with water twice and dried with sodium sulfate, then finally distilled completely. The crude product was purified by chromatography over SiO 2 (hexane:EtOAc, 9:1). The resulting product, pure 5-TMD-2-one (12.5 g) was recrystallized from hexane. MS m/z: 169.12 (M À H)+.
A generalized reaction scheme is presented in Fig. 5.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were found in difference-Fourier maps. Their coordinates were refined freely with U iso parameters set to 1.2U eq of their attached nitrogen atom. To ensure satisfactory refinement of the disordered CF 3 groups, a combination of constraints (EADP in SHELXL) and restraints (SHELXL commands SAME, SADI, SIMU, and RIGU) were employed.